The biochemistry and physiology of the renin-angiotensin system will be examined in vitro and in vivo in experimental animals and in normal and hypertensive man in relation to circulatory homeostasis and fluid and electrolyte balance. The mechanism of action of angiotensin I (AI) converting enzyme will be studied using peptide inhibitors in order to assess the importance of pulmonary and peripheral AI conversion in generating the body's pool of angiotensin II (AII) and investigate the interactions of AI and AII with the adrenergic nervous system, adrenal medulla and arteriolar walls. Labelled peptide analogs of known converting enzyme blockers will be synthesized in order to permit study of the pharmacokinetics of converting enzyme blockers in vivo. Converting enzyme activity will be measured in plasma from normal men and patients with lung disease in an attempt to discover physiologic regulatory mechanisms and possible disorders of AI conversion. The metabolic pathways of AII, including sites, enzymatic mechanisms and functional roles of metabolites will be examined in detail in the intact dog kidney and in single microperfused nephrons of the rat. The role of the heptapeptide des-Asp-angiotensin II (angiotensin III, AIII) in pressure and volume homeostatis will be explored. A sensitive and specific assay for AIII will be developed by combining affinity chromatography and radioimmunoassay and used to measure AIII in plasma and interstitial fluid in various physiologic and pathophysiologic states. The determinants of pressor sensitivity to AII will be studied in vivo by doing AII infusion tests in anesthetized dogs in various states of sodium balance whose endogenous AII production has been blocked using AI converting enzyme inhibitors and in vitro by studying the dynamics of AII binding to smooth muscle cells. Ongoing studies of the humoral determinants of renin release in normal man in relation to renal sodium handling and blood pressure control will be continued. BIBLIOGRAPHIC REFERENCES: Oparil, S. Cutilletta, A.F. and Low, J.: Cardiac hemodynamics and hypertrophy in nerve growth factor antiserum treated spontaneously hypertensive rats. Am.J. Cardiol. 37:161, 1976.